Fig. 3

Simplified scheme of signaling pathways and molecules mediating the formation of brain metastases from melanoma. a Activation of STAT3 in BM can occur via astrocyte-secreted heterodimeric IL23 and leads to the expression of MMP2. The suppressor of cytokine signaling 1 (SOCS1) binds to and inhibits the kinase activity of Janus-kinase 2 (JAK2). The loss or downregulation of SOCS2 in BM may be responsible for increased stat3 activation. b Binding of NGF or pro-NGF induces CD271/p75^NTR -mediated FSCN1 binding or HPSE1 secretion or PI3K/AKT signaling via unknown effectors. c RTKs induce PI3K/AKT signaling or the RAS/RAF cascade. Mutually exclusive mutant (*) RAS (~ 15–20% NRAS mutations) or RAF (~ 40–50% BRAF mutations) activate the extracellular-regulated kinases ERK1/2, which in turn phosphorylate exo70/EXOC7 (filled red circle), the catalytic subunit of the exocyst complex, or blocks expression of PDE5A via brain-2 (BRN2/POU3F2) to regulate actin dynamics. HPSE1 activity induces AKT-signaling, blocked by PTEN or modified by PLEKHA5. d The secretion of CCL17 by astrocytes attracts CCR4⁺ melanoma cells, possibly inducing NFκB-mediated signaling and the regulation of MMP13, CD271 or CCR4 which is in turn regulated via TNFα